Childhood Bone Sarcomas Bone sarcomas comprise a group of several different cancerous tumors of the bone. The most common bone sarcomas diagnosed in children and teens are osteosarcoma and Ewing's sarcoma. More than 1,000 children are diagnosed each year in the United States with some form of bone cancer. There are distinct differences in how different bone sarcomas are treated. Osteosarcoma Osteosarcoma is a malignant tumor of the bone. It is the most common of the bone sarcomas. Scientific advances over the past 25 years have dramatically improved outcome. Advancements in surgery have also improved the quality of life for children and teens diagnosed with osteosarcoma. Who gets osteosarcoma? The peak incidence for osteosarcoma occurs between the ages of 10 and 25 years. This has led researchers to believe that there is an association between the disease and the rapid period of bone growth experienced in adolescents. In adolescents, osteosarcoma is the fourth most common cancer, following leukemias, lymphomas, and brain tumors. The disease is almost twice as common in males as in females and is slightly more common in white children than in black children. In children and teens, 80 percent of these tumors arise in either the end of the thigh bone (femur) closest to the knee or the end of the shin bone (tibia) closest to the knee. It also sometimes appears in the end of the upper arm bone (humerus) nearest the shoulder. Other less common sites are the pelvis, jaw, and ribs. Twenty percent of children diagnosed with this bone tumor have metastases (cancer which has spread to other places in the body) at the time their cancer is found. Of this group, approximately 85 percent have tumors in the lungs. Genetic factors The cause of osteosarcoma is not known. However, persons with Li-Fraumeni syndrome, a rare, inherited disorder, have a higher risk of developing cancers including soft tissue and bone sarcomas. A rare eye cancer of childhood called retinoblastoma is also associated with osteosarcoma. Children who have the inherited form of retinoblastoma have a substantial risk of developing osteosarcoma. The risk appears to be increased by treatment with radiation to the bones of the eye socket. But the increased frequency of osteosarcoma in non-irradiated sites, e.g., arms and legs, indicates a genetic abnormality predisposing the child to these two cancers. When scientists examine osteosarcoma cells from patients who had retinoblastoma, they find that both copies of a gene called RB1 are mutated. The RB1 gene is the same gene that is mutated in retinoblastoma. Environmental factors Radiation is the only known environmental factor believed to lead to increased risk of osteosarcoma. About 3 percent of children diagnosed with the disease have had previous irradiation of the site. Treatment for prior malignancies with certain chemotherapy drugs, such as alkylating agents, may also contribute to the development of secondary osteosarcoma. Osteosarcoma signs and symptoms Osteosarcoma occurs most frequently in the long bones. Symptoms usually include pain, with or without an associated swelling. The affected area may have an increased temperature. Osteosarcoma is often noticed after the child or teen has an incidental injury. It is important to note that the injury did not cause the tumor: it only brought it to attention. The range of motion of joints may be decreased. Often, the child will be limping, since about 80 percent of these tumors are located near the knee. This little girl's knee symptoms didn't seem striking, initially: Leeann was ten years old when she was diagnosed with osteosarcoma in the left femur. I remember feeling total and utter shock. She had been complaining of pain in her knee for a month or so, but since she was physically active playing basketball, baseball, and gymnastics, I assumed it was something minor like a pulled ligament. I also told her more than once that it was just "growing pains." Fortunately, she persisted and we took her to a local orthopedist. The orthopedist asked us to make an appointment with a pediatric orthopedist two and a half hours from home. I knew at this point it was something much more serious than a pulled muscle. Once the initial diagnosis was made, we went into a fog. Symptoms that may indicate the presence of metastatic disease are fever and weight loss. Metastatic disease in the lung is most often asymptomatic. Occasionally, it may cause shortness of breath, chest pain, and coughing. Diagnosis of osteosarcoma Before a diagnosis of osteosarcoma can be reached, specific tests and procedures are performed. This always begins with the physician obtaining the child's medical history and performing a complete physical examination. A complete blood count (CBC) and differential is ordered, along with other bloodwork and a urinalysis. The first imaging studies done are often x-ray films of the area suspected of having a malignancy. Because these tumors have a distinct appearance when viewed on plain films, a radiologist may suspect that osteosarcoma is present based on x-ray alone. In addition, an MRI of the affected bone is almost always done prior to biopsy. MRIs provide accurate information that is used by the surgeon to plan the appropriate surgical intervention. They are also excellent scans for detection of "skip lesions." Skip lesions are areas of disease occurring at different sites but within the same bone as the primary tumor. A definitive diagnosis of osteosarcoma can only be made based on actual tumor tissue. An open biopsy or a needle biopsy removes samples of the mass which are then examined by a pathologist under a microscope. The biopsy should be performed by a physician who has experience in surgery for osteosarcoma. Staging Once osteosarcoma has been diagnosed, more tests are done to determine if the cancer has spread to other parts of the body. Imaging studies that may be performed to check for metastases are computed tomography (CT) of the chest and a bone scan. A bone scan that uses a radiopharmaceutical, called technetium-99m, is frequently ordered to provide the physician with clear images of the entire skeleton. Technetium-99m is very sensitive to osteosarcoma; therefore, these bone scans are particularly helpful in detecting the presence of metastatic disease and skip lesions. It is, however, sensitive to many other normal events, for example, minor strains and injuries to the bone. So an abnormality on the bone scan does not always mean tumor spread. There are two stages for osteosarcoma: Localized. These tumors are limited to the bone of origin, although skip lesions may exist in the same bone. Metastatic. These tumors are found in other parts of the body, including the lungs, other bones, or distant sites. Prognosis Since the 1970s, the treatment of osteosarcoma has improved dramatically. The majority of children and teens now survive the disease, many with limbs still intact. The prognosis and best treatment for each child with osteosarcoma is determined by analysis of several clinical and biologic features. The most significant of all factors used to determine prognosis for the child with osteosarcoma is the extent of the disease at diagnosis and whether it has metastasized or not. For children or teens with localized disease, the following factors are considered: resectability of the tumor, determined by location and tumor size, and response of the tumor to chemotherapy. The prognoses of children or teens with metastatic disease at diagnosis depend on the site of the metastases and the resectability of the metastatic tumors (either at diagnosis or after chemotherapy). Osteosarcoma is much harder to cure if there is metastatic disease. Treatment of osteosarcoma The majority of children and teens with osteosarcoma who receive optimal treatment are cured of the disease. At diagnosis, many parents are confused about how to find the best doctors and treatments for their child. State-of-the-art care is available from physicians who participate in the Children's Cancer Group (CCG) and the Pediatric Oncology Group (POG). These study groups, composed of pediatric surgeons and oncologists, urologists, radiation oncologists, researchers, and nurses, establish the standard of care for patients worldwide, conduct new studies to discover better therapies, and establish follow-up for survivors. They are in the process of merging into one entity called the Children's Oncology Group (COG). If the treatment center you are referred to is a member of one of these groups, you can rest assured that your child will have access to the best thinking on the treatment of pediatric cancers. The oncologist will choose the best treatment or clinical trial based on many factors. For most patients, treatment is chemotherapy, followed by surgery and then more chemotherapy. Osteosarcoma is not very responsive to radiation. Surgery The improvements that have been made in surgical management of osteosarcoma over the past several years have significantly improved the long-term survival rate and the quality of life for children diagnosed with this disease. Surgery is usually undertaken after a period of pre-operative chemotherapy, although some protocols may call for initial surgical resection. Successful surgical resection of the primary tumor most often consists of either limb-salvage surgery or amputation. A surgical procedure called a thoracotomy (opening the chest cavity) is also used to treat children with metastases to the lungs. Surgery for the affected limb doesn't have to keep a child from enjoying an active life: Eric was diagnosed in September 1996 at age fifteen with osteosarcoma in his left femur. He's had chemotherapy and successful limb salvage surgery. Before cancer he was a baseball player, aggressive in-line skater, and a real on-the-go kid. I'm proud to say he took his new limitations very well. He was able to remain very active despite his reconstructed leg. Although high-impact activities were discouraged, he continued to ride his bicycle and go canoeing and hiking and camping in the mountains. He played softball with his friends but preferred to let someone else do his base running. The surgeon chooses the best surgery after considering several factors, including the size, location, and extent of the primary tumor, the presence or absence of distant metastases, the age of the child, skeletal development, and patient and family preferences. This surgery is best done by surgeons who have a great deal of experience treating osteosarcoma. Amputation In recent years, many advances have been made in the surgical management of osteosarcoma. However, some children still require amputation of the affected limb. Amputation involves removal of all or a portion of an arm or a leg. Children with large tumors involving the nerves and blood vessels may not be candidates for limb-salvage procedures. Very young children with lower extremity tumors, as well as those who do not respond well to chemotherapy, may need amputation. In most instances, amputation allows removal of all gross and microscopic disease. In the past, many surgeons felt that removal of the entire affected bone was the safest approach to lasting control of the disease. This was because of a significant rate of recurrence in the remaining stump. However, improved imaging techniques using CT and MRI allow surgeons to view areas of disease with greater accuracy, permitting aggressive surgery while still preserving as much of the affected limb as possible. Children who require amputation need a great deal of rehabilitation and psychological support. While it is traumatic to deal with at any age, osteosarcoma typically occurs during the teenage years, when appearance is especially important to the adolescent's emotional well-being. State-of-the-art prosthetic limbs allow great mobility as well as cosmetic appeal. Studies have been done which show no difference in the quality of life between patients who had amputation and those who had limb-salvage surgery. Limb-salvage surgery Advances made in limb-salvage procedures have enabled this technique to be used with an increasing number of children. The challenge for the surgeon is to remove all evidence of disease while maintaining surrounding nerves and blood vessels. The structural integrity of the bone is then restored through the use of bone grafts or metallic devices. With successful, complete resection, the outcome is equivalent to that of amputation. The benefits of limb-salvage procedures are both functional and psychological. However, limb-sparing surgery is not used if there is any doubt that the surgeon will be able to completely remove the tumor. The first priority is complete surgical excision, even if that requires amputation. Children who have a broken bone at the time of diagnosis may not be good candidates for limb-salvage surgery. Chemotherapy before surgical intervention may cause poor healing of the fracture, which creates added obstacles when attempting limb-sparing techniques. Tumor location, as well as the age of the child, can also dictate amputation as a more suitable curative approach. There are several different approaches to structural reconstruction in limb-salvage surgery. Autologous grafts involve removing a healthy bone from another area of the child's body to replace the diseased bone. Allografts use bone from cadaver donors. Endoprostheses employ a manufactured replacement for the diseased bone, usually made of steel or titanium. This parent describes some of the pros and cons of one type of reconstruction: My daughter was sixteen when she was diagnosed with osteosarcoma. During her surgery, they wrapped a muscle from the back of her calf around to the front to hold the bone graft in place. It left a large open area that was covered by a skin graft from her thigh. It certainly worked in holding her graft in place, but left her leg looking pretty awful (even though we had a plastic surgeon assist with that part of the surgery) and I haven't seen a scar like it on anyone else. They also put small bone slivers from her own bones around the graft sites in hopes of faster grafting, and that apparently worked, as well. She walks much better than they expected: a slight limp but no braces necessary. She never did regain feeling in the bottom of her right foot. Sometimes she thinks amputation would have been better because with a prosthesis she'd be able to run and jump and roller blade and participate in sports, things she can't do now with the bone graft and complete knee replacement. Tumor removal without replacement by a graft or endoprotheses Sometimes the surgeon will perform a procedure known as rotationoplasty when the tumor involves the knee region. This method still requires use of a prosthetic device, but the benefit is that it allows greater functional use of the limb in children requiring removal of the knee. In this procedure, the surgeon removes the affected femur and knee joint, but maintains the connection of the lower leg to the upper thigh. The lower portion of the leg is then rotated 180 degrees and attached to the remaining thigh bone. The ankle serves as a replacement for the surgically removed knee. An artificial limb is then designed to fit over the foot and ankle. This surgery can cause cosmetic and psychosocial difficulties because of the appearance of the reconstructed limb. However, the increased function of the limb after using this technique should be considered. In addition, rotationoplasty can allow a more aggressive surgical removal of a diseased bone, making it a possible alternative to amputation in some cases. Chemotherapy Chemotherapy has greatly improved the long-term survival of children with osteosarcoma. Before the use of chemotherapy, the prognosis was very poor for a child diagnosed with osteosarcoma, despite amputation. This is because many children, including those with no obvious signs of metastatic disease, had microscopic involvement to the lungs at the time of diagnosis. The list of chemotherapy drugs that are used against the disease is shorter than that of many other malignancies. Doxorubicin, high-dose methotrexate with leucovorin rescue, cisplatin, and ifosfamide was among the first combination of chemotherapeutic drugs to improve long-term survival. The use of anticancer drugs as an adjuvant, or addition, to surgery, has led to a survival rate of approximately 70 percent in children with non-metastatic disease at diagnosis. Chemotherapy is given in most instances before and after surgery. Administration of chemotherapy before surgery has been shown to facilitate limb-salvage procedures by allowing tumor shrinkage prior to removal. It can also be used as a prognostic indicator: children who respond well to presurgical chemotherapy have a better prognosis. Other treatments Studies are currently underway that attempt to use the child's immune system to fight osteosarcoma. One of these includes the use of a biologic response modifier known as liposome-encapsulated muramyl tripeptide-phosphatidylethanolamine, or MTP-PE. This biologic agent is used in children with non-metastatic osteosarcoma to treat microscopic disease that may be present in the lungs. MTP-PE activates certain cells of the immune system which attack and destroy osteosarcoma cells. Monoclonal antibodies are also being investigated as a potential therapeutic approach against the disease. It is hoped that this method will allow delivery of anti-cancer drugs directly to the tumor cells. These treatments are still in the early stages, and it will be some time before their long-term efficacy will be shown. Ewing's sarcoma family of tumors Ewing's sarcoma gets its name from the physician who first described it in 1921, Dr. James Ewing. He noted that this bone cancer was different from osteosarcoma because it was particularly sensitive to radiation. For several years, it was felt that Ewing's sarcoma occurred only within the bone; however, other tumors were found within soft tissues and determined to be similar under the microscope. These include extraosseous Ewing's sarcoma (EES) and peripheral primitive neuroectodermal tumor (PPNET). Together, these malignancies are called the Ewing's sarcoma family of tumors (ESFT). Who gets ESFT tumors? Each year, about 150 children are diagnosed in the United States with an ESFT malignancy. Ewing's sarcoma of the bone accounts for 87 percent of these diagnoses, while 8 percent are extraosseous Ewing's sarcoma, and 5 percent are peripheral primitive neuroectodermal tumors. Most ESFT tumors occur between the ages of ten to twenty years. Only 27 percent will be diagnosed before the age of ten years. Boys tend to be diagnosed with this disease more often than girls, and there is a much higher incidence in white children compared to those of any other race. Ninety-six percent of all ESFT tumors are found in white children. The most common areas in which these tumors occur are the pelvis, the thigh bone (femur), the upper arm bone (humerus), and the ribs. Genetic factors ESFT tumors usually don't occur in association with childhood congenital diseases. However, when scientists look at the genetic material (DNA in chromosomes) of an ESFT tumor, more than 90 percent have a translocation between chromosomes 11 and 22 called t(11:22). This shifts a portion of one chromosome to the other, and produces a new protein from the fusion of the two chromosomes. Scientists are studying this protein to try to learn more about ESFT tumors. Environmental factors No environmental factors have been associated with development of ESFT tumors. ESFT signs and symptoms The symptoms of ESFT tumors depend very much on the location of the disease. Almost all children diagnosed with Ewing's sarcoma of the bone will have pain, and more than half will have swelling of the affected area. Approximately 16 percent will have a fracture at the site of disease, and 21 percent will have a fever. A diagnosis is sometimes delayed because the symptoms of an ESFT tumor can be very similar to those of an infection. It is not unusual for several months to pass, once the onset of symptoms has occurred, before the disease is discovered. Children with metastatic disease may seem tired and have unexplained weight loss. If the cancer has spread to areas around the spine, symptoms may include back pain or paralysis. Diagnosis of ESFT For a diagnosis of an ESFT tumor to be reached, the physician will order several tests and procedures. This process always begins with the doctor obtaining the child's medical history and performing a complete physical examination. Several blood tests will be ordered, including a complete blood count (CBC) and differential. Other laboratory studies include the measurement of lactate dehydrogenase (LDH). If there is suspicion that the disease may be neuroblastoma, a urinalysis to measure catecholamine levels may be ordered. Imaging studies will generally begin with x-ray films of the site that is suspected of having a malignancy. A definitive diagnosis of an ESFT tumor cannot be made unless the doctor has confirmation with actual tumor tissue. This may be accomplished with either an excisional biopsy, in which the surgeon will remove the mass completely, an incisional biopsy, in which only a small portion of the tumor is removed for evaluation, or a needle biopsy. Staging Once a diagnosis is made, other tests are done to determine if the disease has spread. This process is called staging. Computed tomography (CT) of the chest, abdomen, and pelvis are usually done to stage the tumor. Magnetic resonance imaging (MRI) provides detailed images which help define the extent of the disease. Radionuclide scanning, or scintigraphy, with technetium-99m methylene diphosphonate (tTc 99m MDP) is used to determine the extent of the primary tumor and also helps to determine the presence of metastatic disease in bone. The doctor may order a gallium scan since Ewing's sarcoma accumulates this radiopharmaceutical very well. The doctor does bilateral bone marrow biopsies and aspirates to determine if the disease has spread to the bone marrow. There are only two stages for ESFT tumors: Localized. These tumors have not spread to distant sites. Metastatic. These tumors have spread to other parts of the body, including the lungs, bones, and bone marrow. Prognosis Treatment for childhood ESFT has steadily improved in the last two decades. In the 1960s, virtually all children with ESFT died, but by the 1990s, the majority of children with localized disease who receive optimal treatment are cured. Like many cancers, the most important prognostic factor for ESFT tumors is the presence or absence of metastatic disease at diagnosis. In those children with localized tumors, the location of the primary site has also been shown to be of prognostic significance. Those with a tumor originating in the pelvic area have a less favorable prognosis than those with tumors originating in the distal bones and ribs. On November 5, 1997, we received a prognosis: metastatic Ewing's sarcoma of the bone. If left untreated, Elizabeth would have two months to live. We were advised to put her on a new form of treatment designed by the Children's Cancer Group. She would then have a little bit better than 20 percent chance of survival. We gave our consent and began our journey into the world of cancer treatment. Treatment of ESFT At diagnosis, many parents are confused about how to find the best doctors and treatments for their child. State-of-the-art care is available from physicians who participate in the Intergroup Ewing's Sarcoma Study, Children's Cancer Group (CCG) and the Pediatric Oncology Group (POG). These study groups, composed of pediatric surgeons and oncologists, urologists, radiation oncologists, researchers, and nurses, establish the standard of care for patients worldwide, conduct new studies to discover better therapies, and establish follow-up for survivors. They are in the process of merging into one entity called the Children's Oncology Group (COG). If the treatment center you are referred to is a member of one of these groups, you can rest assured that your child will have access to the best thinking on the treatment of pediatric cancers. The goal of treatment for ESFT is to cure the child and to maintain as much function of the affected area as possible, as well as minimize the possible long-term effects of treatment. Treatment for an ESFT tumor includes surgery and chemotherapy and, in some circumstances, radiation. When the tumor is completely resected with good margins of normal tissue, radiation is generally not given. Surgery The approach to surgical management of ESFT tumors depends largely on the location of the mass and the impact that resection will have on the function of the affected part of the body. If the tumor is situated in a non-essential bone or soft tissue, it can sometimes be removed without creating deformity or resulting in loss of function. However, the primary site is often found in the extremities, where this approach may not be possible. In addition, sometimes the initial approach must be revised: My son Jeremy had Ewing's in his left distal femur. He was diagnosed at age eleven. He had chemo from February to April of that year ('94) and then limb-salvage surgery in May. He was on crutches for a very long time. They were able to spare his distal growth plate in the initial surgery. However, three surgeries later (problems with the "hardware") they finally screwed bolts into his growth plate. Since then, he has had to have surgery once to shorten his "unaffected" leg. Before the development of limb-salvage surgery and newer radiation techniques, most children with extremity tumors had the affected limb amputated. Many children now have limb-salvage procedures using autologous grafts, allografts, an endoprosthesis, or state-of-the-art radiation therapy to treat their tumor. In some cases, however, amputation is still preferred: When we decided that amputation was the best treatment, we spent the next few weeks talking about it. It was almost as if we were mourning the loss of his leg and foot--saying goodbye to his toes. The surgery to remove his leg just below the hip took fourteen hours. Troy's femur was removed, and the tibia was moved up and flipped to act as the upper leg bone. The foot was amputated. His prosthesis was attached at the knee. I have never regarded my son as handicapped. Troy is able to do almost all things other kids his age enjoy doing. He climbs, rides a bike, skateboards, and even spends time on his boogie board. Today he is a healthy, happy thirteen-year-old. Tumors located in the lungs can often be removed by a procedure called thoracotomy (surgery in which an incision is made to open the chest cavity). Disease located within the ribs sometimes requires the removal of affected bones and replacement with a synthetic material to reconstruct the chest wall. Radiation Radiation is often needed to treat children diagnosed with ESFT tumors. Radiation is used for tumors that cannot be completely resected. Some chest wall tumors are treated with whole-lung irradiation. ESFT tumors are generally treated with doses ranging from 4000 to 5600 cGy, fractioned over a period of four to six weeks. Chemotherapy Before chemotherapy became a standard weapon against ESFT tumors in the 1960s, very few children survived. Chemotherapy improved the long-term survival rate and also facilitated surgical management of the disease by reducing the tumor size before resection. Treatment of Ewing's now includes systemic chemotherapy for all children. This is necessary even for those children with localized disease. The most commonly used combination of chemotherapy drugs includes vincristine, doxorubicin, cyclophosphamide, ifosfamide, etoposide, and dactinomycin. Newest treatment options Much research is being conducted into new treatments for ESFT tumors. Peripheral blood stem cell transplants are being performed at various centers across North America. Gene therapy is being researched as a potential therapy against ESFT tumors. Monoclonal antibodies may soon allow delivery of anti-cancer drugs directly to the tumor cells. To learn about the standard treatment for your child's illness, call (800) 4-CANCER and ask for the PDQ (physician's data query) for osteosarcoma or Ewing's sarcoma/primitive neuroectodermal tumor. These free statements explain the disease, state-of-the-art treatments, and ongoing clinical trials. Two versions are available: one for patients, which uses simple language and contains no statistics, and one for professionals, which is technical, thorough, and includes citations to scientific literature. The PDQ can also be read on the Internet at http://cancernet.nci.nih.gov/. This parent describes an excellent outcome: My daughter Casey was treated for osteosarcoma by an orthopedic oncologist. As soon as she stopped vomiting from chemotherapy, she returned to her beloved cheerleading, took up jazz dancing (she claims it was the best physical therapy), and is now on the varsity springboard diving team at her high school. She sends her orthopedic oncologist photos and videotapes of her doing these things that he claims give him heart pains. But, one day, when he observed her sitting cross-legged in his examining room, he finally admitted that she has had the best physical response of any of his patients and he took a picture of her sitting that way for a brochure. I can't explain to you how wonderful it makes me feel to see this doctor actually glow when he sees Casey (now only once a year)--he calls the whole office together to behold her! This fact sheet was adapted from Childhood Cancer: A Parent's Guide to Solid Tumor Cancers, by Honna Janes-Hodder and Nancy Keene, © 2001 by Patient-Centered Guides. For more information, call (800) 998-9938 or see www.patientcenters.com.